Aim: The aim of the present study was to design, synthesize, and evaluate novel antibacterial agents, derivatives of aryl-4-guanidinomethylbenzoate and N-aryl-4-guanidinomethylbenzamide. Methods: A total of 44 derivatives of aryl-4-guanidinomethylbenzoate (series A) and N-aryl-4-guanidinomethylbenzamide (series B) were synthesized and their antibacterial activities were assessed in vitro against a variety of Gram-positive and Gram-negative bacteria by an agar dilution method. Results: Twelve compounds showed potent bactericidal effects against a panel of Gram-positive germs, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), vancomycin-intermediate Staphylococcus aureus (VISA), and methicillin-resistant coagulase-negative staphylococci (MRCNS), with minimum inhibitory concentrations (MIC) ranging between 0.5 and 8 µg/mL, which were comparable to the MIC values of several marketed antibiotics. They exhibited weak or no activity on the Gram-negative bacteria tested. In addition, these compounds displayed high inhibitory activities towards oligopeptidase B of bacterial origin. Conclusion: In comparison with the previously reported MIC values of several known antibiotics, the derivatives of aryl-4-guanidinomethylbenzoate and N-aryl-4-guanidinomethylbenzamide showed comparable in vitro bactericidal activities against VRE and VISA as linezolid. Their growth inhibitory effects on MRSA were similar to vancomycin, but were less potent than linezolid and vancomycin against MRCNS. This class of compounds may have the potential to be developed into narrow spectrum antibacterial agents against certain drug-resistant strains of bacteria.